Anticoagulant therapy for the thrombotic complications of the antiphospholipid antibody syndrome

Patients with antiphospholipid antibodies (APLA) are at risk of arterial thromboembolism (ATE) or venous thromboembolism (VTE). The true strength of the association between APLA and first TE is unknown as there are no prospective studies of a large, well-characterized inception cohort of matched patients with and without APLA. Thus, evidence-based treatment recommendations for primary prophylaxis of TE in such patients cannot be made. Optimal therapy of patients with recent TE and APLA remains controversial; although there is no doubt that some such patients have a malignant hypercoagulable state characterized by resistance to “usual intensity” anticoagulation; recent evidence suggests that most such patients are adequately treated with “usual therapy”. After warfarin discontinuation, such patients appear to be at increased risk of recurrent TE, as demonstrated in a series of studies of discontinuation of secondary TE prophylaxis in patients with APLA and venous TE (VTE). Because of this increased risk of recurrent TE, after anticoagulants are discontinued, most “experts” recommend extended duration therapeutic dose warfarin for such patients. This paper will briefly review this evidence.     

Endothelial function is impaired in patients with primary antiphospholipid syndrome

INTRODUCTION: The aim of this study was to evaluate endothelial function in patients with primary antiphospholipid syndrome (PAPS). PATIENTS AND METHODS: Flow mediated (FMD) and glyceryl trinitrate (GTN) induced dilation of the right brachial artery were studied in 25 patients with PAPS and 25 controls matched by age, sex and conventional risk factors for atherosclerosis. Fibrinogen, D-dimer, adhesion molecules, tissue plasminogen activator (t-PA) and plasminogen activator inhibitor-1 (PAI-1) antigens and activities were measured. RESULTS: Mean (SD) FMD was significantly lower in PAPS than in controls (8+/-5% vs. 15+/-6%, P<0.001); GTN-induced dilation did not differ between the groups. There was a correlation between the baseline diameter of the brachial artery and duration of the disease (-0.56, P<0.05) and between GTN induced dilation and duration of the disease (0.51, P<0.05). Concentrations of vascular cell adhesion molecule-1 (P<0.001), intracellular adhesion molecule-1 (P<0.001) and fibrinogen (P<0.05) were higher in patients than in controls but no differences were observed for D-dimer, t-PA and PAI-1 antigens and activities. There was correlation between concentration of vascular cell adhesion molecule-1 and FMD (-0.35, P<0.05) and between intracellular adhesion molecule-1 and FMD (-0.41, P<0.05). CONCLUSIONS: This study shows that endothelial function is impaired in patients with primary APS, possibly contributing to accelerated atherosclerosis and thromboembolic complications in these patients.     

Neurological complications of schoenlein-henoch syndrome: contribution of MR to the diagnosis. Case report

In the protean clinical pattern of the Schoenlein-Henoch syndrome the central and peripheral nervous system signs and symptoms are of most uncertain epidemiological importance and of most debatable physiopathological status. In the case reported the contribution of nuclear magnetic resonance to the diagnosis proved to be greater than that of computed tomography because it imaged the CNS lesions.

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Sommario Nell'ambito delle multiformi varietà di espressione clinica della sindrome di Schoenlein-Henoch i segni ed i sintomi a carico del sistema nervoso centrale e periferico sono quelli di più incerta rilevanza epidemiologica e di più discussa interpretazione fisiopatologica. Nel caso clinico riportato il contributo diagnostico della Risonanza Magnetica Nucleare si è dimostrato superiore a quello della Tomografia Computerizzata per la dimostrazione delle lesionia carico del SNC.

     

From antibody to clinical phenotype,the black box of the antiphospholipid syndrome: Pathogenic mechanisms of the antiphospholipid syndrome

The antiphospholipid syndrome (APS) is diagnosed by the combination of vascular thrombosis and/or pregnancy morbidity and the detection of antiphospholipid antibodies (aPLs) in plasma. In the last few years, a great effort has been made to unravel the mechanism by which aPLs cause thrombosis and a vast amount of mechanisms have been proposed. aPLs were proposed to induce a prothrombotic state by influencing the cellular blood compartment, the plasma compartment, the vascular wall and even metabolic pathways beyond the hemostatic system. However, due to the diversity in the mechanisms and the differences in the methodology, the focus of the mechanistical studies in this field seems to be largely diffused. It is hard to imagine that aPLs can exert such a diversity of effects, resulting in either thrombosis and/or pregnancy morbidity and the relationship between aPLs and the clinical manifestations remains to be a mysterious “black box”. In an attempt to get insight in what takes place inside the black box, we have analyzed 126 mechanistical studies on aPLs and discussed differences in the type of antibodies that were used, the involvement of beta2-glycoprotein I (β₂GPI), and the criteria used to diagnose APS patients.     

Hyperglycaemia impairs antithrombin secretion: Possible contribution to the thrombotic risk of diabetes

Recent data support that diabetes might be a conformational disease. Certainly, hyperglycaemia causes a broad range of deleterious effects that might facilitate protein aggregation. We have evaluated the effects of hyperglycaemia on antithrombin, a conformationally sensitive serpin with a potent anticoagulant role. Moreover, these studies might also help to understand the thrombotic risk associated to diabetes. We incubated in vitro plasma and purified antithrombin and human hepatoma cells (HepG2) with methyl-glyoxal and glucose. Moreover, a mouse model of acute diabetes was generated with streptozotocin. Antigen, anti-FXa activity, heparin affinity and conformational features of antithrombin were analysed. Histological and intracellular features and distribution of antithrombin in HepG2 and livers of mice were also evaluated. Hyperglycaemia in vitro induced a transition of antithrombin to a form with low heparin affinity that explained the loss of anticoagulant activity, without generation of abnormal conformers (polymers or latent antithrombin). However, these effects were not observed on circulating antithrombin from diabetic mice. In contrast, hyperglycaemia in vivo had significant effects on intracellular antithrombin, which was retained, forming microaggregates within the lumen of dilated cisterns of the endoplasmic reticulum. These effects explained the moderate type I deficiency observed in diabetic mice. Similar intracellular consequences were observed for another hepatic serpin, α1-antitrypsin. Our data further support that diabetes has conformational effects on structurally sensitive proteins. These effects on antithrombin, the main natural anticoagulant, might contribute to the hypercoagulable status of diabetic patients.     

Increased warfarin consumption and residual fibrin turnover in thrombotic patients with primary antiphospholipid syndrome

Introduction

Anedoctal reports suggest that some thrombotic primary antiphospholipid antibody syndrome (PAPS) patients on oral anticoagulation require higher than average doses to achieve given targets international normalized ratios (INR).

Materials and methods

To test the hypothesis of relative warfarin resistance in thrombotic PAPS and the effect of baseline IgG anticardiolipin antibodies, the cytochrome CYP2C9 and the vitamin K epoxide reductase (VKORC1) haplotypes we compared weekly warfarin consumption of 40 TPAPS (mean age 44 ± 16 years) with that of 65 thrombotic patients with inherited thrombophilia (IT) (mean age 52 ± 18) at similar target INR 2.0-3.0 followed up between January-1994 and January 2003. To investigate an involvement of the epoxidation pathway in this difference and to assess enhanced residual fibrin turnover decarboxylated prothrombin (PIVKA-II) and D-dimers (DD) were cross-sectionally investigated in the same patients between March and May 2008.

Results

CEX7 and VKORC1 polymorphisms explained 45.1% of the variability in warfarin consumption, whose age-adjusted mean weekly consumption was greater in PAPS than IT (27.62 vs 21.24 mg, p = 0.03). In PAPS baseline IgG aCL and VKORC1 predicted weekly warfarin consumption (p = 0.028 and p = 0.024). IgG β₂GPI and warfarin dose independently predicted plasma PIVKA-II (p = 0.01 and p = 0.02). Age and sex adjusted DD was greater in PAPS than IT (132 ± 34 vs 83 ± 37 mg/dl, p = 0.03).

Conclusions

Thrombotic PAPS exhibit a degree of warfarin resistance partly accounted by antiphospholipid antibodies and are in a state of enhanced fibrin turnover despite oral anticoagulation that might have implications for re-thrombosis and atherosclerosis.     

Chorea and high antiphospholipid antibodies: probable primary antiphospholipid syndrome

A young man presented with generalized chorea as the first manifestation of probable primary antiphospholipid syndrome. He was well till 3 months before admission when he started to have involuntary, choreiform movements involving all extremities, the head and the bulbar muscles. Apart from these movements his physical examination was otherwise unremarkable. Laboratory investigations revealed mild thrombocytopenia, high partial thromboplastin time (PTT) only partially corrected by the addition of normal plasma, false positive syphilis serology, weakly positive antinuclear antibody and a high level of IgG anticardiolipin antibodies. Brain magnetic resonance imaging (MRI) showed multiple scattered small areas of high signal intensity on T2 weighted image in the area of centrum semiovale bilaterally. The patient was started on aspirin and prednisone with rapid symptomatic improvement. Despite the difficulty in proving the association between chorea and the high antiphospholipid antibodies, chorea appears in this case to be the initial symptom of primary antiphospholipid syndrome and we suggest screening for antiphospholipid antibodies in unexplained cases of chorea.     

Different types of antiphospholipid antibodies in AIDS: a comparison with syphilis and the antiphospholipid syndrome.

Alloimmune antiphospholipid antibodies react with phospholipids and are an epiphenomenon of an infectious disease. Most autoimmune antiphospholipid antibodies recognise phospholipid-protein complexes or proteins, such as beta2 glycoprotein I or prothrombin and are related to the clinical features of the antiphospholipid syndrome. Lupus anticoagulant, anticardiolipin antibodies, antiprothrombin, and anti-beta2 glycoprotein I antibodies were studied in 61 human immunodeficiency virus (HIV) patients, 55 syphilis patients, and 45 selected patients with antiphospholipid syndrome. Lupus anticoagulant was present in 72% of HIV and 81% of antiphospholipid syndrome patients. None of the syphilis patients had lupus anticoagulant. Anticardiolipin antibodies were found at comparable prevalence in the three groups (HIV 67%, syphilis 67%, antiphospholipid syndrome 84%). HIV had more frequently anti-beta2 glycoprotein I (13%) and antiprothrombin (12%) antibodies than syphilis (0 and 4%, respectively), but significantly less than antiphospholipid syndrome (61 and 40%, respectively). Autoimmune antiphospholipid antibodies in HIV without clinical features of antiphospholipid syndrome might be a reflex of the immunological chaos and/or the constant antigenic virus stimulus.     

Mechanisms of antiphospholipid antibody-associated pregnancy complications

Women with antiphospholipid syndrome (APS) and antiphospholipid antibodies (aPL) are at high risk for recurrent spontaneous miscarriage and late pregnancy complications, such as preeclampsia and preterm labor. Recent clinical and experimental observations suggest that the pathophysiology of pregnancy failure in patients with APS may involve inflammation at the maternal-fetal interface and disruption of normal trophoblast function and survival, rather than a pro-thrombotic event. While treatment with heparin and aspirin from early pregnancy has been shown to significantly increase the live birth rate in recurrent miscarriage patients with APS, the incidence of severe late pregnancy complications still remains high. This review will discuss what is currently known about the mechanisms by which aPL may compromise pregnancy outcome.     

Sneddon's syndrome: an antiphospholipid antibody syndrome?

A 44-year-old woman with livedo reticularis, multiple ischemic strokes, and transient ischemic attacks (Sneddon's syndrome) had antiphospholipid antibodies--the lupus anticoagulant and anticardiolipin antibodies. This patient provides support for the hypothesis that these antibodies are involved in the pathogenesis of this rare but now potentially treatable disorder.     

Atypical onset of antiphospholipid syndrome in pregnancy: a case report

BACKGROUND: We present a case of an atypical onset of antiphospholipid syndrome (APS). CASE: A woman in her 15th week gestation had a thrombosis of an unknown cerebral cavernoma, which was successfully removed. Twenty-six days after, she was admitted for a severe pain in right hypochondrium and a second class HELLP syndrome was diagnosed. Two days after, she had a fetal loss. After 1 month, laboratory tests revealed high level of antiphospholipid antibodies. At the same time, she developed a spontaneous thrombosis at her right arm. After 6 weeks, antiphospholipid antibodies, tested again, result positive. CONCLUSION: Antiphospholipid antibodies often cause pregnancy complications, but, to our knowledge, this is the first report of an association of antiphospholipid antibodies, with cerebral cavernoma thrombosis and early onset HELLP syndrome.     

Involvement of microparticles in diabetic vascular complications

Type 2 diabetes mellitus (T2DM) is associated with increased coagulability and vascular complications. Circulating microparticles (MPs) are involved in thrombosis, inflammation, and angiogenesis. However, the role of MPs in T2DM vascular complications is unclear. We characterised the cell origin and pro-coagulant profiles of MPs obtained from 41 healthy controls and 123 T2DM patients with coronary artery disease, retinopathy and foot ulcers. The effects of MPs on endothelial cell coagulability and tube formation were evaluated. Patients with severe diabetic foot ulcers expressed the highest levels of MPs originated from platelet and endothelial cells and negatively-charged phospholipid-bearing MPs. MP coagulability, calculated from MP tissue factor (TF) and TF pathway inhibitor (TFPI) ratio, was low in healthy controls and in diabetic retinopathy patients (<0.7) but high in patients with coronary artery disease and foot ulcers (>1.8, p≥0.002). MPs of all T2DM patients induced a more than two-fold increase in endothelial cell TF (antigen and gene expression) but did not affect TFPI levels. Tube networks were longest and most stable in endothelial cells that were incubated with MPs of healthy controls, whereas no tube formation occurred in MPs of diabetic patients with coronary artery disease. MPs of diabetic retinopathy and diabetic foot ulcer patients induced branched tube networks that were unstable and collapsed over time. This study demonstrates that MP characteristics are related to the specific type of vascular complications and may serve as a bio-marker for the pro- coagulant state and vascular pathology in patients with T2DM.